Experimental evolution of complex traits

项目摘要 通过自然选择的进化导致生物适应其环境，但也涉及权衡。 今天影响人类的许多复杂疾病是我们过去进化的历史产物。一个更好的 对适应过程的理解可能为对抗复杂疾病提供新的工具。然而， 我们在基因型和表型水平上对适应动态的认识存在相当大的差距， 这在很大程度上是由于推断过去的选择对人类种群的影响的挑战。长期 这项建议的目标是阐明适应的分子基础，使用一种创新的，有性生殖的 异交酵母（Saccharomyces cerevisiae）实验室系统。实验进化提供了一个强大的 一种检验关于适应的假设的方法，研究人员观察种群在真实的时间内的进化， 控制条件。通过基因组测序，可以在基因组测序期间从种群中取样遗传变异。 适应过程;这种技术被称为“进化和重新排序”，或E&R。最近的E&R工作 酵母实验室系统已经推进了基本的进化问题，例如通过提供强大的 证据表明，预先存在的遗传变异驱动适应，而不是有益的新突变。此外，它发现 遗传多样性的长期稳定维持是常见的，即使在选择很强的情况下。建筑 在这些初步发现的基础上，其他的问题正在被测试，比如进化的结果是什么， 从复杂的选择环境，包括波动或其他动态选择压力，以及什么 基因表达在一系列时间尺度上对适应性变化的影响。该提案利用了 MIRA的灵活的研究目标，因为它将支持多个酵母E&R项目。每个人都将进一步 了解一般的适应动力学，也将提供特定的特点具体的见解。的性状 这项建议特别关注的是晚年生育率。衰老，或存活率和生育力的下降， 老年痴呆症是一个很好的例子，说明了人类由于进化的权衡而面临的复杂疾病。 该应用程序中的初步数据表明，通过只选择最老的细胞来繁殖， 世代，酵母种群进化到比对照种群寿命更长，并在更晚的年龄保持生育能力。这 提供了一个令人兴奋的潜力，解剖遗传基础的长寿和晚年生育能力，和新的 预计研究前景将因此变得可实现。这项研究意义重大，因为 它有望纵向推进和扩大对健康基础的自然遗传变异的理解， 与疾病相关的表型，特别是与晚年生殖成功相关的表型。 最终，这些知识有可能为个性化医疗方法的发展提供信息， 和/或基因疗法，这将导致各种改善的健康结果。

PROJECT SUMMARY Evolution via natural selection results in organisms adapted to their environment, but also involves trade-offs. Many complex diseases affecting humans today are historical artifacts of our past evolution. Thus, a better understanding of the process of adaptation may provide new tools to combat complex disease. And yet there are considerable gaps in our knowledge of the dynamics of adaptation at the level of genotype and phenotype, in large part due to the challenges of inferring the effects of past selection on human populations. The long-term goal of this proposal is to elucidate the molecular basis of adaptation using an innovative, sexually-reproducing laboratory system of outcrossing yeast (Saccharomyces cerevisiae). Experimental evolution offers a powerful method to test hypotheses about adaptation as investigators observe populations evolve in real time under controlled conditions. With genome sequencing, genetic variation can be sampled from populations during the process of adaptation; this technique is called “Evolve-and-Resequence”, or E&R. Recent E&R work with this yeast laboratory system has advanced fundamental evolutionary questions, for example by providing strong evidence that preexisting genetic variation drives adaptation, rather than beneficial new mutations. Also, it finds that the stable long-term maintenance of genetic diversity is common, even when selection is strong. Building upon these initial discoveries, additional questions are being tested, such as what evolutionary outcomes result from complex selection environments involving fluctuating or otherwise dynamic selection pressures, and what influence gene expression has on adaptive change, over a range of time scales. This proposal takes advantage of MIRA’s flexible research goals, as it would support multiple yeast E&R projects. Each will further understanding of general adaptative dynamics, and will also deliver specific insights into particular traits. A trait of special interest to this proposal is late-life fertility. Senescence, or the decline in survival and fertility with advancing age, is a good example of a complex disease facing humans as a result of evolutionary trade-offs. Preliminary data in this application show that through selecting only the oldest cells to reproduce over many generations, yeast populations evolve to live longer and remain fertile at later ages than control populations. This provides an exciting potential to dissect the genetic basis underlying longevity and late-life fertility, and new research horizons are expected to become attainable as a result. The proposed research is significant, because it is expected to vertically advance and expand understanding of the natural genetic variation underlying healthy versus disease-related phenotypes, and specifically for phenotypes related to late-life reproductive success. Ultimately, such knowledge has the potential to inform the development of approaches in personalized medicine, and/or gene therapies, that will lead to a variety of improved health outcomes.